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The following information helps you to find FDA Alerts and Pharmacist’s Applications to Practice quickly and easily. In cooperation with the Food and Drug Administration (FDA), and as a service to our members, HOPA periodically distributes information about newly approved therapies for cancer patients from FDA’s Office of Oncology Drug Products Director, Dr. Richard Pazdur to inform oncologists and professionals in oncology-related fields in a timely manner. Links to product labels will take you to relevant clinical information on the indication, contraindications, dosing, and safety. In sending this information, HOPA does not endorse any product or therapy and does not take any position on the safety or efficacy of the product or therapy described.

Along with HOPA’s Publications Committee, members also review new drug updates and provide analysis and research on the application of these new drugs or indications. Pharmacist’s Applications to Practice, or PAP, are listed after drugs that include the additional analysis.

https://www.accessdata.fda.gov/drugsatfda_docs/label/2020/213973s000lbl.pdf.

On May 15, 2020, the Food and Drug Administration approved ripretinib (QINLOCK, Deciphera Pharmaceuticals, LLC.), for adult patients with advanced gastrointestinal stromal tumor (GIST) who have received prior treatment with 3 or more kinase inhibitors, including imatinib.

Efficacy was evaluated in INVICTUS (NCT03353753), an international, multi-center, randomized (2:1), double-blind, placebo-controlled trial in 129 patients with GIST who were previously treated with imatinib, sunitinib, and regorafenib. Patients received ripretinib150 mg or placebo orally once daily until disease progression or unacceptable toxicity. Crossover was permitted at disease progression for patients randomized to receive placebo.

The major efficacy outcome measure was progression-free survival (PFS) based on assessment by blinded independent central review (BICR) using modified RECIST 1.1 in which lymph nodes and bone lesions were not target lesions and a progressively growing new tumor nodule within a pre-existing tumor mass must meet specific criteria to be considered unequivocal evidence of progression. Additional efficacy outcome measures included overall response rate (ORR) by BICR and overall survival (OS).

The trial demonstrated a statistically significant improvement in PFS for patients in the ripretinib arm compared with those in the placebo arm (HR 0.15; 95% CI: 0.09, 0.25; p<0.0001). The median PFS was 6.3 months (95% CI: 4.6, 6.9) for ripretinib compared with 1.0 month (95% CI: 0.9, 1.7) for placebo. The ORR was 9% (95% CI: 4.2, 18) in the ripretinib arm compared with 0% (95% CI: 0, 8) in the placebo arm, though this difference was not statistically significant. The median OS in the ripretinib arm was 15.1 months (95% CI: 12.3, 15.1) compared with 6.6 months (95% CI: 4.1, 11.6) in the placebo arm with a HR of 0.36 (95% CI: 0.21, 0.62), though OS was not evaluated for statistical significance as a result of the sequential testing procedure for the secondary endpoints (i.e., PFS, then ORR, then OS).

The most common adverse reactions (≥20%) with ripretinib were alopecia, fatigue, nausea, abdominal pain, constipation, myalgia, diarrhea, decreased appetite, palmar-plantar erythrodysesthesia, and vomiting. Other important risks of ripretinib include new primary cutaneous malignancies, hypertension, and cardiac dysfunction.

The recommended ripretinib dose is 150 mg orally once daily with or without food.

View full prescribing information for QINLOCK.

FDA collaborated with the Australian Therapeutic Goods Administration (TGA) and Health Canada on the review of this application as part of Project Orbis. FDA approved ripretinib three months ahead of schedule. The review of the applications is ongoing for the Australian TGA and Health Canada.

This review used the Real-Time Oncology Review, which streamlined data submission prior to the filing of the entire clinical application, and the Assessment Aid, a voluntary submission from the applicant to facilitate the FDA’s assessment.

FDA granted this application priority review, fast track, and breakthrough therapy designation. Ripretinib also received orphan drug designation. A description of FDA expedited programs is in the Guidance for Industry: Expedited Programs for Serious Conditions-Drugs and Biologics.

Healthcare professionals should report all serious adverse events suspected to be associated with the use of any medicine and device to FDA’s MedWatch Reporting System or by calling 1-800-FDA-1088.

For assistance with single-patient INDs for investigational oncology products, healthcare professionals may contact OCE’s Project Facilitate at 240-402-0004 or email This email address is being protected from spambots. You need JavaScript enabled to view it..

For information on the COVID-19 pandemic, see the following resources:

Follow the Oncology Center of Excellence on Twitter @FDAOncologyExternal Link Disclaimer.


Pharmacist’s Applications to Practice

Ripretinib for the treatment of advanced gastrointestinal stromal tumors (GIST) in adults who have previously received treatment with ≥ 3 kinase inhibitors, including imatinib.

Author: Kristen Nymberg, PharmD
Inpatient/Outpatient Genitourinary Medical Oncology Pharmacy Specialist
The Ohio State University Wexner Medical Center/The James Cancer Hospital and Solove Research Institute Columbus, OH

What is the potential role for ripretinib in the treatment of advanced GIST?

  • Ripretinib is approved for adults with advanced GIST who have previously received treatment with ≥ 3 kinase inhibitors, including imatinib.1
  • Ripretinib functions as a switch control tyrosine kinase inhibitor (TKI) that inhibits KIT proto-oncogene receptor tyrosine kinase (KIT) and platelet derived growth factor receptor A (PDGFRA) kinase signaling. Kinase activation and subsequent signaling requires the interaction between the activation switch and the switch pocket. Ripretinib binds to both the activation switch and the switch pocket and locks the kinases in the inactive state, which prevents downstream signaling and therefore inhibits cancer cell proliferation and survival. In addition to inhibiting KIT and PDGFRA, ripretinib also inhibits PDGFRB, TIE2, VEGFR2, and BRAF.1
  • Imatinib is the primary therapy for unresectable or metastatic GIST. Following imatinib, sunitinib is approved in the second line setting and regorafenib is approved in the third line setting.  Progressive disease can result from acquired drug resistance and is typically due to mutations in KIT or PDGFRA.2-5 Ripretinib is active against both wild type and mutant forms of KIT and PDGFRA, which gives it a role in the treatment of advanced GIST after progression on other tyrosine kinase inhibitors.1
  • Ripretinib versus placebo was evaluated in the INVICTUS trial which was a double-blind, placebo-controlled, phase 3 study.6
    • Methods
      • Patients were included if they had advanced GIST and had progressed on at least imatinib, sunitinib, and regorafenib, or had documented intolerance to any of these agents despite dose modifications.
      • Patients were randomly assigned in a 2:1 ratio to receive either ripretinib 150 mg orally once daily or matching placebo. All patients also received best supportive care.
      • The primary endpoint was progression-free survival (PFS). Secondary endpoints included: objective response rate (ORR), overall survival (OS), and safety.
    • Results
      • 129 patients were randomly assigned to receive ripretinib (n = 85) or placebo (n = 44).
      • Efficacy: ripretinib vs. placebo
        • Median PFS: 6.3 months vs. 1.0 months (HR 0.15, 95% CI 0.09–0.25; p < 0.0001)
        • ORR: 9% vs. 0% (p = 0.0504)
        • Median OS: 15.1 months vs. 6.6 months (HR 0.36, 95% CI 0.21-0.62)
      • Safety
        • The most common grade 1-2 treatment-related adverse reactions in the ripretinib group (occurring in ≥ 20% of patients) included alopecia (49%), myalgia (27%), nausea (25%), fatigue (24%), palmar–plantar erythrodysesthesia (also known as hand–foot syndrome, 21%,), and diarrhea (20%).

What role can the pharmacist play in the management of patients on ripretinib?

  • Ripretinib is prescribed as 150 mg (three 50 mg tablets) once daily until disease progression or unacceptable toxicity. It dispensed in a bottle with ninety 50 mg tablets.1
  • Ripretinib may be taken with or without food and should be administered at the same time each day.
    • In the event of a missed dose, the patient may take the missed dose if less than 8 hours have passed since the missed scheduled dose.
    • If vomiting occurs after taking ripretinib, the patient should not take an additional dose and should continue with the next scheduled dose.
  • The tablets should be swallowed whole and cannot be crushed.
  • Ripretinib is a major substrate of CYP3A4. It is recommended to avoid concomitant use with strong CYP3A4 inducers and monitor for increased adverse effects when ripretinib is used in combination with strong CYP3A4 inhibitors.
  • Ripretinib has not been studied in patients with severe renal impairment or moderate-severe hepatic impairment.
    • There are no available dose modifications for renal or hepatic impairment.
  • It is recommended to assess ejection fraction prior to ripretinib initiation and during treatment as clinically indicated.
  • Blood pressure should be monitored prior to treatment initiation, as well as during treatment. Ripretinib should not be started in patients with uncontrolled hypertension.
  • Patients should undergo a dermatologic evaluation prior to starting ripretinib and routinely during treatment. Suspicious skin lesions should be excised and sent for dermatopathologic evaluation.
  • Guidelines are available in the package insert regarding dose reductions for palmar–plantar erythrodysesthesia, hypertension, left ventricular systolic dysfunction, arthralgia or myalgia, and any other grade 3 or 4 toxicities.
    • First dose reduction: 100 mg once daily.
    • Permanently discontinue ripretinib in patients who are unable to tolerate 100 mg once daily.
  • A patient education sheet on ripretinib produced by the Association of Community Cancer Centers, HOPA, the National Community Oncology Dispensing Association, and the Oncology Nursing Society can be found at https://www.oralchemoedsheets.com/sheets/Ripretinib_Patient_Education.pdf.

Clinical Pearls

  • Ripretinib therapy should be held for at least 1 week prior to an elective surgery and should continue to be held for at least 2 weeks after a major surgery and until adequate wound healing has occurred.
  • Ripretinib may cause fetal harm and should not be given to females who are pregnant. Patients should use effective contraception during therapy and for at least one week after the last dose of ripretinib.
  • Ripretinib should be handled as a hazardous medication and be stored in its original container.
  • Copay assistance for ripretinib is available through the Deciphera AccessPoint. Additional information can be found at: https://www.decipheraaccesspoint.com/patient/getting-qinlock.

References

  1. Qinlock (ripretinib) [prescribing information]. Waltham, MA: Deciphera Pharmaceuticals, LLC; May 2020.
  2. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology. Soft Tissue Sarcoma. Version 2.2020 (May 28, 2020). Available at https://www.nccn.org/professionals/physician_gls/pdf/sarcoma.pdf.
  3. Demetri GD, von Mehren M, Blanke CD, Van den Abbeele AD, Eisenberg B, et al. Efficacy and Safety of Imatinib Mesylate in Advanced Gastrointestinal Stromal Tumors. N Engl J Med. 2002; 347: 472-480. doi: 10.1056/NEJMoa020461.
  4. Demetri GD, van Oosterom AT, Garrett CR, Blackstein ME, Shah MH, et al. Efficacy and safety of sunitinib in patients with advanced gastrointestinal stromal tumour after failure of imatinib: a randomised controlled trial. Lancet. 2006; 368(9544): 1329-38. doi: 10.1016/S0140-6736(06)69446-4.
  5. Demetri GD, Reichardt P, Kang YK, Blay JY, Rutkowski, et al. Efficacy and safety of regorafenib for advanced gastrointestinal stromal tumours after failure of imatinib and sunitinib (GRID): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013; 381(9863): 295-302. doi: 10.1016/S0140-6736(12)61857-1. Blay JY, Serrano C, Heinrich MC, Zalcberg J, Bauer S, et al. Ripretinib in patients with advanced gastrointestinal stromal tumours (INVICTUS): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Oncol. 2
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